This proposal seeks support to continue our progress in the design and synthesis of halogenated derivatives and analogs of steroid hormones that retain affinity for their cellular receptors and that can be prepared by procedures that permit the incorporation of radioactive iodine ([123]I) and fluorine ([18]F). Target compounds are androgens and glucocorticoids. The radiohalogenated androgens will have great utility for ln-vivo imaging of androgen receptor (AR) containing tissues where iodine-123 labeled compounds can be used in single photon emission computed tomography (SPECT) and fluorine-18 labeled androgens will be important because of their applications in positron emission tomography (PET). These sensitive methods are important for the detection of androgen responsive tumors such as prostate cancer as well as the metastases that may follow. Thus the labeled compounds are expected to be useful in monitoring the progress of cancer patients in therapy. Labeled compounds with glucocorticoid activity will be valuable in mapping and imaging of glucocorticoid receptor (GR) rich regions of the brain using SPECT ([123]1labeled compounds) and PET ([18]F-labeled compounds). Such studies are of increasing importance in defining and understanding the role and function of corticosteroids in the brain where they are reputed to be involved in psychiatric disorders such as depression and in the management of stress. This laboratory has successfully pursued the development of radiolabeled progestins, androgens and, more recently, glucocorticoids. This proposal seeks to optimize our synthetic work on androgens as well as to develop ester derivatives and deuterated analogs designed to improve tissue uptake and metabolic stability, thus leading to more effective imaging agents. Similarly we seek to expand upon and extend our success in the development of high affinity ligands for the glucocorticoid receptor by optimizing synthetic procedures, exploring new ligands and incorporating features designed to improve tissue uptake. Thus, the synthesis of several potential iodinated or fluorinated ligands for the androgen and glucocorticoid receptors, as well as derivatives thereof, will be pursued and optimized. These compounds will be tested in this collaborative study for their ability to compete for binding to the entire array of steroid receptors. The same precursors of these nonradioactive halogenated steroid analogs will be used to synthesize the radiohalogenated versions of those analogs and derivatives which show favorable binding characteristics. These radioactive steroids will be studied in a battery of in vitro and in vivo hormonal assays to ascertain their ability to concentrate in tissues in a receptor mediated fashion. This proposal specifically requests funding for the synthesis and other chemical studies of the nonradioactive ligands and their precursors.